Many pharmaceutical solids can exist in different physical forms, e.g. in an amorphous form, in one or several crystal form(s) (e.g. anhydrous or solvated forms), in the form of mixture of different crystal forms, or as a mixture of an amorphous form and crystal form(s).
An amorphous form is a form in which a three-dimensional long-range order does not exist. In the amorphous form the position of the molecules relative to one another are essentially random, i.e. without regular arrangement of the molecules on a lattice structure. Amorphous and disordered materials often have improved properties, but generating and stabilising this state can be a big challenge.
A crystal or crystalline form is the form in which the position of the molecules relative to one another is organised according to a three-dimensional lattice structure. Crystalline forms typically include polymorphs and pseudopolymorphs. Polymorphs are different crystalline forms of the same compound resulting from different arrangement of the molecules in the solid state. Different polymorphs have different crystal structures due to a different packing of the molecules in the lattice. This results in a different crystal symmetry and/or unit cell parameters. Polymorphs differ from each other in their physicochemical parameters but not in their chemical composition. Polymorphism is usually difficult to control and poses challenges to the galenists. Pseudopolymorphs, also referred to as solvates, are a particular case of solid state crystalline forms in which either stoichiometric or non-stoichiometric amounts of solvent molecules are present or incorporated into the lattice structure of the compound. A water solvate is also referred to as a hydrate.
Solid state chemistry is of interest to the pharmaceutical industry and especially to those involved in the development of suitable dosage forms. For example, solid state transformations may seriously impact the stability of pharmaceutical drugs (shelf-life). A metastable pharmaceutical solid form can change into a crystalline structure (e.g. from amorphous to crystalline) or solvate/desolvate in response to changes in environmental conditions, processing, or over time.
Different crystal forms or amorphous form of the same drug may have substantial differences in such pharmaceutically important properties as dissolution rates, thermodynamic solubility and bioavailability. The rate of dissolution of an active ingredient in a patient's stomach fluid may have therapeutic consequences since it imposes an upper limit on the rate at which an orally-administered active ingredient may reach the patient's bloodstream. The rate of dissolution is thus a consideration in formulating solid dosage forms and liquid medicaments such as syrups and elixirs.
Likewise, different crystals or amorphous form may have different processing properties, such as hygroscopicity, flowability, compactation, and the like, which could affect their suitability as active pharmaceuticals for commercial production.
During the clinical development of pharmaceutical drugs, if the polymorphic form is not held constant, the exact dosage form used or studied may not be comparable from one lot to another. It is also desirable to have processes for producing a compound with the selected polymorphic form in high purity when the compound is used in clinical studies or commercial products since impurities present may produce undesired toxicological effects. Certain polymorphic forms may exhibit enhanced thermodynamic stability or may be more readily manufactured in high purity in large quantities, and thus are more suitable for inclusion in pharmaceutical formulations.
JNJ-26481585 has the following structure:

The compound is an inhibitor of histone deacetylase (HDAC).
WO 2006/010750 published on 2 Feb. 2006 discloses an amorphous form of JNJ-26481585.C2HF3O2 salt and a di-HCl salt and processes for obtaining them.
The synthesis of JNJ-26481585.C2HF3O2 salt as originally described in WO 97/21701, is presented in scheme 1.
Therein, in step 1 intermediates of formula (III) were prepared by reacting an intermediate of formula (I) with the carboxaldehyde of formula (II), in the presence of sodium tetrahydroborate, in methanol.
In step 2 intermediates of formula (IV) were prepared by reacting an intermediate of formula (III) with sodium hydroxide in ethanol.
In step 3, intermediates of formula (V) were prepared by reacting an intermediate of formula (IV) with O-(tetrahydro-2H-pyran-2-yl)-hydroxylamine, in the presence of appropriate reagents such as N′-(ethylcarbonimidoyl)-N,N-dimethyl-1,3-propanediamine, monohydrochloride (EDC) and 1-hydroxy-1H-benzotriazole (HOBT). The reaction was performed in a mixture of dichloromethane and tetrahydrofuran.
In step 4, the hydroxamic acid C2HF3O2 salt of formula (VI) was prepared by reacting the intermediate of formula (V), with trifluoro acetic acid. Said reaction was performed in methanol.

Alternatively, the JNJ-26481585. 2HCl salt as originally described in WO 97/21701, was prepared by reacting the intermediate of formula (III), with hydroxylamine, in the presence of sodium hydroxide. Said reaction is performed in methanol, further conversion to the di-HCl salt was prepared in ethanol.
The process disclosed in WO 2006/010750 is unsuitable for large scale production as the consequence of low yields and high amount of impurities in the different process steps, which consequently requires several chromatographic steps. The purification of compounds using chromatography is expensive and environmentally unfriendly due to solvent consumption and the specialised equipment required to perform a large scale chromatography.
The problem solved by the present invention is the provision of novel crystalline forms of mono-HCl salts and a mono-HCl salt hydrate of JNJ-26481585. Another aspect of the present invention is a process wherein the novel crystalline HCl salt and HCl salt hydrate form are obtained in high yield and high purity. The advantageous properties of the present HCl forms are superior physicochemical properties including its non-hygroscopic nature and chemical stability enabling drugability of this compound.